Although the regulation of hepatic cholesterol synthesis is probably multifactorial, the magnitude of the enterohepatic circulation of cholesterol and bile salts may play a key role. Because of the interdependence of bile salts and cholesterol metabolism, it has been possible to separate their direct effects on the activity of the rate limitizing enzyme of cholesterol synthesis 3-hydroxy 3-methyl glutaryl coenzyme A (HMG CoA) reductase. To do this, we have utilized an isolated perfused liver. We have found that bile salts do not seem to be direct regulators of hepatic HMG CoA reductase. We plan to utilize the same system to assay the ability of other proposed sterol and lipoprotein regulators of cholesterol synthesis to affect the activity of this regulatory enzyme. We also propose to extend previous studies delineating the defect in the regulation of cholesterol homeostasis induced by bile duct ligation.